Healthcare-associated infections (HAI) constitute a major public health concern as they are common and associated with both high morbidity and mortality rates and high healthcare costs1,2. 54% of all HAI occurred in people aged 65 or over3. Risk factors for HAI vary with the infection site, healthcare setting, and patient age. We previously reported that among patients aged 70 years or over, invasive procedures and comorbidities assessed using the Cumulative Illness Rating Scale for Geriatrics (CIRS-G), were strong risk factors for HAI4. In elderly individuals, the increased susceptibility to severe infections and decreased efficacy of vaccination may reflect ageing of the immune system, called immunosenescence, which involves nearly all the components of the immune system5,6.
Two main lines of hypothesis are currently debated to explain immunosenescence. On the one hand, a major role has been ascribed to the progressive decline in naive circulating T-cell counts (paralleling the involution of the thymus), expansion of memory T-cells, and accumulation of terminally differentiated effector CD8 T-cells7. Cytomegalovirus (CMV) is also considered crucial among the repeated antigenic stimuli responsible for the accumulation of oligoclonal effector CD8 T cells8. The Immune Risk Phenotype (IRP) coined by Pawelec et al9 takes into account these alterations. It includes inversion of CD4/CD8 ratio, and expansion of CD28 negative CD8 T-cells, associated with positive CMV serology10. In a previous study, at baseline, patients with subsequent HAI indeed showed lower naive CD4+ and CD8+ T cell counts, and higher counts of CD28−CD8+ T cells11. However, parameters alterations remained within normal range. IRP measurement showed that patients exhibiting the IRP had a higher rate of nosocomial infection, although only in the lung.
On the other hand, low-grade chronic inflammation is often encountered in elderly people12. The mechanisms that underlie this ageing-associated heightened level of basal inflammation might involve changes in numbers and functions of innate immune cells, leading to inefficient response as well as decreased tolerance. Chronic inflammation is commonly encountered in atherosclerosis13, Alzheimer's disease14, and HIV infection15. Microbial translocation has recently been suggested to have a key role in driving this persistent immune activation in individuals with chronic HIV infection16. Microbial translocation consists in (i) the translocation of commensal microbial products from the intestinal lumen, which is now known to occur in healthy conditions; and (ii) transfer into the systemic circulation (in the absence of overt bacteraemia), which is abnormal and is accompanied by a persistent immune activation leading to low grade systemic inflammatory response17.
Recent evidence suggests that disruption of the intestinal barrier is associated with aging18. The first event leading to microbial translocation consists in the alteration of the epithelial barrier, monitored using plasma intestinal-type fatty acid-binding protein (I-FABP) concentration, which reflects apoptosis of the epithelial cell layer19. Microbial products are physiologically controlled by the gut immune system and do not reach periphery. When the gut immune system cannot complete its firewall function, microbial translocation occurs. Once in the circulation, microbial products can stimulate innate cells such as monocytes and macrophages. Endotoxin (lipopolysaccharide, LPS), a component present at the membrane of Gram-negative bacteria binds to several different extracellular and cell surface proteins—the LPS-binding protein (LBP), CD14, MD-2, and Toll-like receptor (TLR)-4. After LPS stimulation, activation of monocytes/macrophages leads to the shedding of surface CD14. soluble CD14 (sCD14) released into blood is elevated in patients with infection and is reported to increase in severity dependent manner20,21.
Determining a patient's susceptibility to nosocomial infections is therefore essential in order to be able to offer personalized management and to endeavour to minimise additional risks of a fatal outcome. There is therefore a true need for other immunological markers with which it is possible to obtain easy, fast prediction of a patient's susceptibility to nosocomial infections. The ability to identify persons the most at risk of contracting a nosocomial infection would allow the setting up of better adapted and better targeted preventive therapy.
Moreover, deterioration of immune function is a prominent hallmark of aging and is only partially explainable by a loss of naïve and central memory CD4 T cells due to thymic involution. Defects in both the innate and adaptive immune system of the elderly have been described and include changes in immune cell-subsets abundance and relative frequencies, altered haematopoiesis, impairments in antigen presentation, decreased B cell as well as T cell proliferation, a reduced TCR repertoire and defect in antibody production (Weiskopf et al., 2009). Ultimately these alterations result in a sharp decline in the response to new and persisting antigens also called as immunosenescence as previously mentioned.
Thus it is not surprising that infectious diseases are one of the major causes of mortality in those over the age of 65 and that protective vaccination of the elderly is more difficult to establish than in younger individuals (Goodwin, 2006).
Due to the complexity of the immune system, studies of immunosenescence often only investigate one or a few variables of an individual's immune system. This has made it difficult to draw general conclusions about the phenomena being described or how they might relate to each other. Individuals who suffer from an impaired immune function generally face the risk of increased morbidity and mortality. This is particularly relevant for older individuals who show a reduced response to vaccination (Strindhall et al., 2007).
Active immunization and activation of T cell-mediated as well as humoral immune response can be achieved through the administration of immunogenic material or vaccines. Vaccination seeks to prevent, ameliorate or even treat against the harmful effects of pathogens and carcinogens, and regular vaccination has become an integral part of preventive medicine. Unfortunately, following vaccination, older individuals often don't develop a fully functioning adaptive immune response, as would be evidenced by a strong antibody production against an introduced immunogen, and, thus, do not obtain the benefits of long-lasting protection against recurring diseases.
Accordingly, one of the most challenging topics facing the maintenance of good health and longevity is the identification of immunocompromised individuals who might appear healthy, but who have an underlying, undetected impairment of immune function and, so, face the risk of increased morbidity and mortality. Additionally, predicting with a very high accuracy whether an individual will respond appropriately to active vaccination and become protected against recurring diseases is a primordial issue for developing personalized treatment plans and optimal immunizations schedules for these patients.